Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain ...the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT reference: (CAG)n-CAA-CAG, since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region (CAG)n-CAG-CAG. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36–39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.
Detecting and classifying factors that contribute to age-related balance decline are essential for targeted interventions. Dynamic postural tests that challenge neuromuscular balance control are ...important to detect subtle deficits that affect functional balance in healthy aging.
How does healthy aging affect specific components of dynamic postural control as measured by the simplified Star Excursion Balance Test (SEBT)?
Twenty healthy younger (18–39 years) and twenty healthy older (58–74 years) adults performed the standardized simplified SEBT, which involved standing on one leg and reaching the contralateral leg as far as possible in the anterior, posteromedial, and posterolateral directions. Optical motion capture was used to quantify the maximum reach distance normalized by body height (%H) for three repeated trials in each direction per leg. Linear mixed effects models and pairwise comparisons of estimated marginal means were used to assess differences (p < 0.05) in normalized maximum reach distance by age group, reach direction, and leg dominance. Intersubject and intrasubject variability were also assessed by age group using coefficients of variation (CV).
Healthy older adults had less dynamic postural control compared to younger adults, with shorter reach distances in the anterior (7.9 %), posteromedial (15.8 %), and posterolateral (30.0 %) directions (p < 0.05). Leg dominance and sex did not significantly affect SEBT score for either age group (p > 0.05). Low intrasubject variability (CV<0.25 %) was found for repeated trials in both the older and younger participants. Therefore, the comparatively higher intersubject variability (Range CV=8–25 %) was mostly attributed to differences in SEBT performance across participants.
Quantifying dynamic postural control in healthy older adults in a clinical setting is important for early detection of balance decline and guiding targeted and effective treatment. These results support that the simplified SEBT is more challenging for healthy older adults, who may benefit from dynamic postural training to mitigate age-related decline.
•The SEBT reliably detects balance decline with healthy aging (60+ years).•Posterior unilateral leg movements were most challenging for older adults.•SEBT learning capacity and leg symmetry were similar across age groups.
Introduction New mutations for Huntington disease (HD) occur due to CAG repeat instability of intermediate alleles (IA). IAs have between 27 and 35 CAG repeats, a range just below the disease ...threshold of 36 repeats. While they usually do not confer the HD phenotype, IAs are prone to paternal germline CAG repeat instability. Consequently, they may expand into the HD range upon transmission to the next generation, producing a new mutation. Quantified risk estimates for IA repeat instability are extremely limited but needed to inform clinical practice. Methods Using small-pool PCR of sperm DNA from Caucasian men, we examined the frequency and magnitude of CAG repeat instability across the entire range of intermediate CAG sizes. The CAG size-specific risk estimates generated are based on the largest sample size ever examined, including 30 IAs and 18 198 sperm. Results Our findings demonstrate a significant risk of new mutations. While all intermediate CAG sizes demonstrated repeat expansion into the HD range, alleles with 34 and 35 CAG repeats were associated with the highest risk of a new mutation (2.4% and 21.0%, respectively). IAs with ≥33 CAG repeats showed a dramatic increase in the frequency of instability and a switch towards a preponderance of repeat expansions over contractions. Conclusions These data provide novel insights into the origins of new mutations for HD. The CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.
Music resonates through the works of Randolph Stow (1935-2010), with landscape, sounds, and words entwined across his elegant and lyrical output. Just as the author describes Shakespeare as having ...words for every emotion, so has Stow a song for every situation, with specific pieces of music used to locate fiction in time and place. Here, Richards talks about the sound and music in the works of Randolph Stow. Music in performance has a strong presence in his writings, from domestic gatherings to country music, Christian worship and indigenous rituals.
Since the introduction of genome sequencing in medicine, the factors involved in deciding how to integrate this technology into population screening programs such as Newborn Screening (NBS) have been ...widely debated. In Australia, participation in NBS is not mandatory, but over 99.9% of parents elect to uptake this screening. Gauging stakeholder attitudes towards potential changes to NBS is vital in maintaining this high participation rate. The current study aimed to determine the knowledge and attitudes of Australian parents and health professionals to the incorporation of genomic sequencing into NBS programs. Participants were surveyed online in 2016 using surveys adapted from previous studies. The majority of parents (90%) self-reported some knowledge of NBS, with 77% expressing an interest in NBS using the new technology. This was significantly lower than those who would utilise NBS using current technologies (99%). Although, many health professionals (62%) felt that new technologies should currently not be used as an adjunct to NBS, 79% foresaw the use of genomic sequencing in NBS by 2026. However, for genomic sequencing to be considered, practical and technical challenges as well as parent information needs were identified including the need for accurate interpretation of data; pre-and post-test counselling; and appropriate parental consent and opt-out process. Therefore, although some support for implementing genomic sequencing into Australian NBS does exist, there is a need for further investigation into the ethical, social, legal and practical implications of introducing this new technology as a replacement to current NBS methods.
Juvenile Huntington disease Geevasinga, Nimeshan; Richards, Fiona H; Jones, Kristi J ...
Journal of paediatrics and child health,
September 2006, 2006-Sep, 2006-09-00, 20060901, Volume:
42, Issue:
9
Journal Article
Peer reviewed
: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder related to expansion of a triplet repeat sequence in the huntington gene on chromosome 4. Adult HD usually presents ...with chorea and personality changes. Juvenile HD is far less common and presents with parkinsonism, dystonia and seizures. We report a case of juvenile HD, showing extreme anticipation, in which diagnosis was delayed because of failure to recognise the significance of the family history and the characteristic clinical and radiologic features of this condition.
The Goat-God in England Richards, Fiona
The D. H. Lawrence review,
04/2015, Volume:
40, Issue:
1
Journal Article
Peer reviewed
In addition to its mysterious, forest connections, Bax's The Happy Forest sits alongside the literary representations of a benign, musical Pan and his relatives: the "friend and helper" in The Wind ...in the Willows, the faun discovered in Wiltshire in Forster's "The Curate's Friend," 1907), and the mysterious, gentle figure in Walter de la Mare's poem "They Told Me." The romanticising of the goat-god was taken to extremes by the artist Frederick Leighton, whose 1856 painting, Pan, goes so far as to remove any trace of hooves. Ireland was prone to self-doubt and questioning, and across his life suffered a number of problematic sexual relationships. ...it is perhaps not surprising that the Pan myth appealed to him on many levels. ...the parallel fifths that start in bar 5 are a recurring feature of Ireland's 'pagan' works. To effect the disappearance of Pan, Ireland returns to the original sustained string chords and flute motif, now played an octave higher by the piccolo. ...while the first situation returns, it is changed timbrally, with the otherworldly tinkling keyboard sound of the celesta marking the end of the experience in the landscape.
The Englishness of Randolph Stow Richards, Fiona
Journal of the Association for the Study of Australian Literature : JASAL,
10/2014, Volume:
14, Issue:
5
Journal Article
Peer reviewed
The second song, 'Green mooned the white lady,' is a ballad in four rhyming strophes, much distorted in the music, in which we are given a hint of the later significance of the colours green and ...white to Stow: Green mooned the white lady of silvered Sydney town -O, stately as a candle-end, all in her winding-gown; apple-pale and like a spider's egg her dainty muslin face and her moonstones new polished with a moon-clout of lace. Stow worked on the new novel in 1983, finishing it despite the distractions of an excellent spring: 'the sun is pouring in the window of my top room, and birds are chirruping away. . . it's distracting me rather from my book-it suits me best to work while the nights are long and cold and dark, and I had hoped to have it finished, or nearly, by now (Letter to mother, 28 April 1983). There are links with Stow's former home towns of Fremantle and Geraldton; the Western Australian and Essex towns saw huge cargo vessels in a working port, and Harwich's lighthouse out at sea was an English version of Fremantle's lighthouse. Stow had an excellent ear for languages, and had begun his researches into the Suffolk dialect by working in the local pub some ten years earlier (Letter to mother, 20 Aug 1973). ...Harry speaks in a distinctive local dialect, the particular words that Stow creates meticulously preserved across the novel, for example: whass what's hooman human redooce reduce goo go knoo know hoom home stoodent student The Suburbs of Hell was shortlisted for East Anglian book of the year in 1984, the prizegiving event aptly held in a literary Suffolk venue, the Angel hotel in Bury St Edmunds, where Dickens's Mr Pickwick stayed.
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